The major goal of our proposed project is to advance the development of novel compounds for the treatment of amyloidosis and other protein aggregation diseases. Preliminary work demonstrated that two chalcones inhibited amyloid fibril formation, in vitro, and that further work is warranted. The amyloid diseases that arise from nonimmunoglobulin proteins include adult onset diabetes (type II diabetes), Alzheimer's disease, Down's syndrome, systemic familial amyloidosis, senile amyloid disease and beta 2-microglobulin (dialysis associated) amyloidosis. Effective therapeutic agents that prevent protein aggregation in these diseases have not been developed to date. A commercial market of significant size exists for drugs that treat protein aggregation diseases. It is estimated that 10 million people worldwide suffer from Alzheimer's disease, 6% of the total population have been diagnosed with type II diabetes and that 1/1000 people in developed countries die annually from amyloidosis. In our continuing research efforts to discover small molecules for the treatment of protein disorders caused by protein aggregation, we developed an economical and convenient high-throughput method for screening compounds against fibril formation in microwell plates and identified a number of chalcone molecules as inhibitors of amyloid fibril formation in the in vitro assay. During our Phase I research program, novel chalcones will be designed, based on the molecular modeling analysis, synthesized using a parallel synthesis approach and screened for the inhibitory activity against amyloid fibril formation using LEN VL protein. Furthermore, mutants of the LEN VL protein will be generated for the identification and confirmation of chalcone binding sites, based on molecular modeling analysis. The successful results obtained from this Phase I program will be the foundation of our SBIR Phase II studies. It is anticipated that, at the conclusion of our Phase II program, not only can an ideal candidate be selected for full IND-directed preclincial studies leading to an IND submission and initiation of clinical trials in the SBIR Phase Ill program, but also and, perhaps more importantly, the knowledge gained and technology developed will be applicable and be extended to other protein aggregation diseases.